Benzimidazole derivatives have been known for their anti-ulcer activities as inhibitors of gastric acid secretion. For example, omeprazole, which has the formula of 5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-1H-benzi midazole), is known for its activity as an inhibitor of H.sup.+ K.sup.+ -ATPase and the proton pump in the gastric mucosa and can be used for the treatment of gastric and duodenal ulcers (Pilbrant and Cederberg, Scand. J. Gastroenterology (1985)20:113-120). The information of omeprazole can be found U.S. Pat. No. 4,255,431, U.S. Pat. No. 4,786,505, and EPO 124495. Lansoprazole, which has the formula of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimid azole, is useful for prophylaxis and therapy of digestive ulcers (e.g., gastric ulcer, duodenal ulcer) and gastritis. Its empirical formula is C.sub.16 H.sub.14 F.sub.3 N.sub.3 O.sub.2 S with a molecular weight of 369.37. The information of lansoprazole can be found U.S. Pat. No. 4,628,098, U.S. Pat. No. 4,689,333, and U.S. Pat. No. 5,026,560.
Omeprazole is very slightly soluble in water, but very soluble in alkaline solutions as the negatively charged ion. It is an ampholyte with pK.sub.a.about.4 (pyridinium) and 8.8 (benzimidazole). Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166.degree. C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water.
According to Pilbrant and Cederberg, Scand. J. Gastroenterology (1985) 20:113-120, omeprazole is susceptible to degradation/-transformation in acid and neutral media. The rate of degradation proceeds with a half-life of less than 10 minutes at pH-values below 4. At pH 6.5 the half-life of degradation is 18 hours; at pH 11 about 300 days.
Due to the acidic gastric condition, a pharmaceutical dosage form of omeprazole must be coated with an enteric coating to prevent omeprazole from premature contact with gastric juice. However, ordinary enteric coatings are also made of acidic compounds. Therefore, if omeprazole is directly covered with the conventional enteric coating, the dosage form may not only become badly discolored but also decreased in omeprazole content with the passage of time.
To overcome the acidic labile problem and to prolong the storage stability of omeprazole, it is generally recommended to mix omeprazole with an alkaline material so as to create a high pH value for the drug. For instance, U.S. Pat. No. 4,738,974 describes the alkaline salts of omeprazole which include Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.2+, Ca.sup.2+, Ti.sup.4+, N.sup.+ (R.sup.1).sub.4 or guanidinium salts.
Alternatively, U.S. Pat. No. 4,786,505 describes an oral dosage form of omeprazole, where omeprazole is mixed with an alkaline reacting substance to create a "micro-pH" around each omeprazole particle of not less than pH=7, preferably not less than pH=8. The alkaline substances described in U.S. Pat. No. 4,786,505 include the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances, such as Al.sub.2 O.sub.3.6MgO.CO.sub.2.12H.sub.2 O, (Mg.sub.6 Al.sub.2 (OH)16CO.sub.3.4H.sub.2 O), MgO.Al.sub.2 O.sub.3.2SiO.sub.2.nH.sub.2 O) or similar compounds; organic pH-buffering substances such as trihydroxymethylaminomethane or other similar pH-buffering substances. The high pH-value of omeprazole can be achieved by using an alkaline reacting salt of omeprazole as described in U.S. Pat. No. 4,738,974.
U.S. Pat. No. 5,232,706 describes an oral dosage form of omeprazole which contains a nucleus formed by a mixture of omeprazole or an alkali salt of omeprazole with a first basic compound, a first coating which contains at least an excipient and a second basic compound, and an enteric coating. The basic compounds referred to in U.S. Pat. No. 5,232,706 are sodium, potassium, magnesium, calcium, aluminum or dihydroxyaluminium salts of amino acids, such as glycocoll, glutamic acid, or lysine, or a pyridine carboxylic acids such as nicotinic acid, or organic bases such as guanidine.
Due to the insolubility of omeprazole in water, most of the omeprazole formulations are prepared by mixing the powder form of omeprazole with various kinds of binders, excipients and carriers. For example, U.S. Pat. No. 4,786,505 describes the preparation of the omeprazole core by mixing omeprazole with alkaline reacting substances to form a powder mixture, followed by formulating the powder mixture into small beads, i.e., pellets, tablets, hard gelatine or soft gelatine capsules by conventional pharmaceutical procedures, i.e., by pressing through an extruder and spheronized to pellets.
U.S. Pat. No. 5,385,739 discloses omeprazole microgranules where the powder form of omeprazole is diluted with a substantially equal amount of mannitol powder, together with sodium lauryl sulfate and carboxymethylstarch, so as to produce a homogeneous and stable dilute powder.
U.S. Pat. No. 5,026,560 describes a formulation of making spherical granules containing omeprazole or lansoprazole. The formulation contains a spherical granule which has a core coated with a binder and spraying powder containing the drug and low substituted hydroxypropylcellulose.
In the invention to be described, novel orally administered pharmaceutical formulations of omeprazole or lansoprazole will be described. These formulations are distinctively different from those of the patents described above: First, the invention uses a free base of omeprazole or lansoprazole instead of the alkaline salt form of the drug. Second, the free base of omeprazole or lansoprazole is mixed with a non-ionic surfactant and water to form an emulsion, rather than a powder mix, which then can be sprayed and dried onto an inert core to form a granule. Third, the invention demonstrates that it is not necessary to mix the free base of omeprazole or lansoprazole with any alkaline substance in order to create a fully bioavailable dosage form. In fact, the omeprazole formulations in which omeprazole is not mixed with any alkaline substance display equal or better dissolution rate than the commercially available omeprazole formulation such as prilosec where omeprazole is mixed with an alkaline substance.